RESUMEN
The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1G93A mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1G93A mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.
RESUMEN
BACKGROUND: Cardiac gene therapies lack effective delivery methods to the myocardium. While direct injection has demonstrated success over a small region, homogenous gene expression requires many injections over a large area. To address this need, we developed a minimally invasive flexible parallel wire robot for epicardial interventions. To accurately deploy it onto the beating heart, an introducer mechanism is required. METHODS: Two mechanisms are presented. Assessment of the robot's positioning, procedure time, and pericardium insertion forces are performed on an artificial beating heart. RESULTS: Successful positioning was demonstrated. The mean procedure time was 230 ± 7 seconds for mechanism I and 259 ± 4 seconds for mechanism II. The mean pericardium insertion force was 2.2 ± 0.4 N anteriorly and 3.1 ± 0.4 N posteriorly. CONCLUSION: Introducer mechanisms demonstrate feasibility in facilitating the robot's deployment on the epicardium. Pericardium insertion forces and procedure times are consistent and reasonable.